Microporous hydrophilic membrane

ABSTRACT

A hydrophilic microporous membrane comprising a thermoplastic resin, having been subjected to hydrophilizing treatment and having a maximum pore size of 0 to 100 nm, wherein when 3 wt % bovine immunoglobulin having a monomer ratio of 80 wt % or more is filtered at a constant pressure of 0.3 MPa, an average permeation rate (liter/m 2 /h) for 5 minutes from the start of filtration (briefly referred to as globulin permeation rate A) satisfies the following formula (1) and an average permeation rate (liter/m 2 /h) for 5 minutes from the time point of 55 minutes after the start of filtration (briefly referred to as globulin permeation rate B) satisfies the following formula (2):
 
Globulin permeation rate  A &gt;0.0015 ×maximum pore size (nm) 2.75     (1)
 
Globulin permeation rate  B /globulin permeation rate  A &gt;0.2 .   (2)

TECHNICAL FIELD

The present invention relates to a hydrophilic microporous membranesuitable for removing microparticles such as viruses.

BACKGROUND ART

Recently in the refining process of a plasma derivative or abiopharmaceutical, there is a need for technology for removingpathogenic agents such as a virus and a pathogenic protein in order toenhance safety. Among the methods for removing pathogenic agents such asa virus is a membrane filtration method. Since the separation operationis conducted, in this membrane filtration method, according to the sizeof the particles based on the sieve principle, the method is efficaciousfor all the pathogenic agents irrespective of the type of pathogenicorganism as well as the chemical or thermal characteristics of thepathogenic organism. Therefore, industrial utilization of the removal ofpathogenic agents using the membrane filtration method has beenprevailing in recent years.

Since infection with an infectious virus among pathogenic agents maycause serious diseases, removal of contaminating viruses is highlyrequired. Types of viruses include smallest viruses, such as parvovirus,with a diameter of about 18 to 24 nm, medium-sized viruses, such asJapanese encephalitis virus, with a diameter of about 40 to 45 nm andrelatively large viruses, such as HIV, with a diameter of about 80 to100 nm, etc. In order to remove these virus groups physically by themembrane filtration method, a microporous membrane having a pore size ofabout 10 to 100 nm is required, and particularly the needs for removingsmall viruses such as parvovirus are increasing in recent years.

In the meantime, when the membrane filtration method is applied in therefining process of a plasma derivative or a biopharmaceutical, it isdesirable not only to enhance the virus removal ability but to allowrapid permeation of a large quantity of physiologically activesubstances in order to improve productivity.

However, when a subject to be removed is a small virus like parvovirus,since its size is extremely small, as small as 18 to 24 nm, it wasdifficult to satisfy both of the virus removal performance and theamount and rate of permeation of physiologically active substances byconventional technology.

That is, conventional microporous membranes have drawbacks that they canallow permeation of high-molecular-weight physiologically activesubstances, such as human immunoglobulin and Factor VIII, at asufficient permeation rate while they cannot remove small viruses suchas parvovirus; or they can remove small viruses such as parvovirus whilethey cannot allow permeation of high-molecular-weight physiologicallyactive substances, such as human immunoglobulin and Factor VIII, at asubstantial permeation rate.

International Publication WO91/16968 pamphlet discloses a processcomprising immersing a membrane with a solution containing apolymerization initiator and a hydrophilic monomer, allowingpolymerization within micropores, thereby adhering a hydrophilic resinto the surface of the micropores. This method, however, has a defectthat the hydrophilic resin merely adheres to the surface of themicropores, and therefore, part of the adhering hydrophilic resin may bedissolved out upon washing out low-molecular weight substances generatedin the reaction and hydrophilicity of the membrane may be easily lost.In addition, if a cross-linking agent is used in a large amount andcopolymerization is performed in order to prevent dissolution-out, highpermeability will not be attained for protein solutions.

JP-A-07-265674 describes a polyvinylidene fluoride film having lowadsorptivity for goat immunoglobulin which can effectively remove smallparticles from a solution. It is described that this film is useful forremoving viruses from the solution. According to the Examples thereof,however, this hydrophilic film shows a low adsorptivity for goatimmunoglobulin, and does not have sufficient permeability forphysiologically active substances such as globulin comparable to thepresent invention.

JP-A-62-179540 describes a hydrophilic hollow fiber porous membranecomprising a hydrophilic hollow fiber porous membrane composed ofpolyolefin and side chains containing a neutral hydroxyl group graftedto the membrane. The Examples thereof, however, only describe ahydrophilic microporous membrane having an average pore size of 0.1 to0.16 μm and does not describe a small pore sized microporous membranehaving a maximum pore size of 10 to 100 μm.

JP-A-07-505830 describes a process which comprises irradiatinghydrophobic microporous membrane of polyolefin or partially fluorinatedpolyolefin, etc. with ultraviolet ray and polymerizing a bifunctionalmonomer which has two reactive groups. According to the above-describedmethod, however, hydrophilicity is lost due to cross-linking inhydrophilic diffusive layer and sufficient filtration rate cannot beattained for a protein solution.

International Publication WO01/14047 pamphlet describes a filtrationmembrane for physiologically active substances wherein the logarithmicremoving ratio for parvovirus is three or more and the permeation ratiofor bovine immunoglobulin having a monomer ratio of 80% or more is 70%or more. However, the main membrane disclosed here comprises hollowfibers made of cellulose, and since the mechanical strength when it iswet with water is low, filtration pressure cannot be made high, andtherefore, it is very difficult to achieve a high permeation rate.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a hydrophilicmicroporous membrane which has high removing ability for small virusessuch as parvovirus, and allows permeation of physiologically activehigh-molecular-weight substances, such as globulin and Factor VIII, at ahigh rate and in large quantities.

The present inventors have conducted intensive studies for attaining theabove-described object and consequently have completed the presentinvention.

That is, the present invention is as follows:

-   1. A hydrophilic microporous membrane comprising a thermoplastic    resin, having been subjected to hydrophilizing treatment and having    a maximum pore size of 10 to 100 nm, wherein when 3 wt % bovine    immunoglobulin having a monomer ratio of 80 wt % or more is filtered    at a constant pressure of 0.3 MPa, an average permeation rate    (liter/m²/h) for 5 minutes from the start of filtration (briefly    referred to as globulin permeation rate A) satisfies the following    formula (1) and an average permeation rate (liter/m²/h) for 5    minutes from the time point of 55 minutes after the start of    filtration (briefly referred to as globulin permeation rate B)    satisfies the following formula (2):    Globulin permeation rate A>0.0015×maximum pore size (nm)^(2.75)      (1)    Globulin permeation rate B/globulin permeation rate A>0.2   (2).-   2. The hydrophilic microporous membrane according to the above 1    having a receding contact angle of water of 0 to 20 degrees.-   3. The hydrophilic microporous membrane according to the above 1 or    2, wherein a logarithmic reduction value of porcine parvovirus at    the time point by which 55 liter/m² has been permeated from the    start of filtration is 3 or more.-   4. The hydrophilic microporous membrane according to any of the    above 1 to 3, wherein both of a logarithmic reduction value of    porcine parvovirus at the time point by which 5 liter/m² has been    permeated from the start of filtration and a logarithmic reduction    value of porcine parvovirus at the time point by which further 5    liter/m² has been permeated after 50 liter/m² is permeated are 3 or    more.-   5. The hydrophilic microporous membrane according to any of the    above 1 to 4, wherein an accumulated permeation volume in three    hours after the start of filtration is 50 liter/m² or more when 3 wt    % bovine immunoglobulin having a monomer ratio of 80 wt % or more is    filtered at a constant pressure of 0.3 MPa.-   6. The hydrophilic microporous membrane according to any of the    above 1 to 5, wherein the above-described microporous membrane    containing a thermoplastic resin is a microporous membrane having a    coarse structure layer with a higher open pore ratio and a fine    structure layer with a lower open pore ratio, and the    above-described coarse structure layer exists on at least one side    of the membrane surface and has a thickness of 2 μm or more and the    thickness of the above-described fine structure layer is 50% or more    of the whole membrane thickness, and the above-described coarse    structure layer and the above-described fine structure layer are    formed in one piece.-   7. The hydrophilic microporous membrane according to the above 6,    wherein the thickness of the above-described coarse structure layer    is 3 μm or more.-   8. The hydrophilic microporous membrane according to the above 6,    wherein the thickness of the above-described coarse structure layer    is 5 μm or more.-   9. The hydrophilic microporous membrane according to any of the    above 1 to 8, wherein the above-described thermoplastic resin is    polyvinylidene fluoride.-   10. The hydrophilic microporous membrane according to any of the    above 1 to 9, wherein the above-described hydrophilizing treatment    is a graft polymerization reaction of a hydrophilic vinyl monomer    having one vinyl group to the surface of the pores of the    hydrophilic microporous membrane.-   11. The hydrophilic microporous membrane according to the above 10,    wherein the above-described hydrophilic vinyl monomer contains a    hydroxyl group.-   12. The hydrophilic microporous membrane according to any of the    above 1 to 11, wherein an adsorption amount per 1 g of the membrane    is 3 mg or less when dead-end filtration at a constant pressure of    0.3 MPa is performed using a 0.01 wt % bovine immunoglobulin    solution and a filtrate of 50 liter/m² from the start of filtration    is collected.-   13. The hydrophilic microporous membrane according to any of the    above 1 to 12 for use in removing viruses from a liquid containing a    physiologically active substance.-   14. A hydrophilic microporous membrane, characterized in that both    of a logarithmic reduction value of porcine parvovirus at the time    point by which 5 liter/m² has been permeated from the start of    filtration and a logarithmic reduction value of porcine parvovirus    at the time point by which further 5 liter/m² has been permeated    after 50 liter/m² is permeated are 3 or more, and when 3 wt % bovine    immunoglobulin having a monomer ratio of 80 wt % or more is filtered    at a constant pressure of 0.3 MPa, an average permeation rate    (liter/m²/h) for 5 minutes from the start of filtration (briefly    referred to as globulin permeation rate A) satisfies the following    formula (1) and an average permeation rate (liter/m²/h) for 5    minutes from the time point of 55 minutes after the start of    filtration (briefly referred to as globulin permeation rate B)    satisfies the following formula (2):    Globulin permeation rate A>0.0015×maximum pore size (nm)^(2.75)      (1)    Globulin permeation rate B/globulin permeation rate A>0.2   (2).

BEST MODE FOR CARRYING OUT THE INVENTION

The maximum pore size of the hydrophilic microporous membrane of thepresent invention measured by the bubble point method is preferably 10nm or more and more preferably 15 nm or more from the viewpoint ofpermeability of physiologically active substances such as globulin andfiltration rate. The upper limit of the maximum pore size measured bythe bubble point method is preferably 100 nm or less, and although itvaries depending on the size of the virus and the like to be removed, itis preferably 70 nm or less for removing medium-sized viruses such asJapanese encephalitis virus, and particularly 36 nm or less when theobject to be removed is a small virus such as parvovirus. The maximumpore size as used herein is the value measured by the bubble pointmethod based on ASTM F316-86.

It is preferable that a skin layer does not exist on the surface of thehydrophilic microporous membrane of the present invention. If a skinlayer exists, suspending substances contained in the solution containingphysiologically active substances such as protein accumulate on themembrane surface, and accordingly a rapid fall in the permeationcapability may occur. The skin layer as used herein refers to a layerwhich exists adjacent to the membrane surface, and whose pore size issmaller compared with the inside of the membrane, and the thicknessthereof is usually 1 μm or less.

The hydrophilic microporous membrane of the present invention has anaverage permeation rate (liter/m²/h) for 5 minutes from the start offiltration (hereinafter briefly referred to as globulin permeation rateA) when 3 wt % bovine immunoglobulin having a monomer ratio of 80 wt %or more is filtered at a constant pressure of 0.3 MPa which satisfiesthe following formula (1):Globulin permeation rate A>0.0015×maximum pore size (nm)^(2.75)   (1).

That is, the globulin permeation rate A of the hydrophilic microporousmembrane of the present invention should be more than 0.0015×maximumpore size (nm)^(2.75), preferably not less than 0.0015×maximum pore size(nm)^(2.80), more preferably not less than 0.0015×maximum pore size(nm)^(2.85), most preferably not less than 0.0015×maximum pore size(nm)^(2.90). When the globulin permeation rate A is more than0.0015×maximum pore size (nm)^(2.75), sufficient permeation rate tocarry out removing of viruses in the production of plasma derivatives,biopharmaceuticals, etc. on an industrial scale is securable.

In addition, the hydrophilic microporous membrane of the presentinvention should have a globulin permeation rate A and an averagepermeation rate (liter/m²/h) for 5 minutes from the time point of 55minutes after the start of filtration (hereinafter briefly referred toas globulin permeation rate B) when 3 wt % bovine immunoglobulin havinga monomer ratio of 80 wt % or more is filtered at a constant pressure of0.3 MPa which satisfies the following formula (2):Globulin permeation rate B/globulin permeation rate A>0.2   (2).

In the hydrophilic microporous membrane of the present invention,globulin permeation rate B/globulin permeation rate A (hereinafterbriefly referred to as the ratio of filtration rates) is preferably 0.3or more, and more preferably 0.4 or more. If the ratio of filtrationrate is more than 0.2, filtration rate can be kept sufficiently andremoving of viruses in the production of plasma derivatives,biopharmaceuticals, etc. on an industrial scale is carried out.

The hydrophilic microporous membrane of the present invention preferablyhas a logarithmic reduction value of porcine parvovirus at the timepoint by which 55 liter/m² has been filtered from the start offiltration (hereinafter referred to as the 0 to 55 liter/m² filteredtime) is 3 or more, and more preferably 3.5 or more, and most preferably4 or more. When logarithmic reduction value of porcine parvovirus at the0 to 55 liter/m² filtered time is 3 or more, it can be equal to the useas a virus removal filter for removing small viruses such as humanparvovirus B19 and poliomyelitis virus from a solution containingphysiologically active substances. Furthermore, the fact that smallviruses such as human parvovirus B19 and poliomyelitis virus can beremoved means that larger viruses such as hepatitis C and HIV can beremoved with still higher probability.

In addition, although a virus concentration in a filtrate may varydepending on a filtered volume, a membrane with no or a small, if any,decreasing ratio in the virus removal ability as the filtered volumeincreases is naturally desired. The hydrophilic microporous membrane ofthe present invention preferably has both of the logarithmic reductionvalue of porcine parvovirus at the time point by which 5 liter/m² hasbeen filtered from the start of filtration (hereinafter referred to asthe 0 to 5 liter/m² filtered time) and the logarithmic reduction valueof porcine parvovirus at the time point by which further 5 liter/m² hasbeen filtered after 50 liter/m² is filtered (hereinafter referred to asthe 50 to 55 liter/m² filtered time) of 3 or more, and more preferably3.5 or more, and most preferably 4 or more. The fact that each of theporcine parvovirus at 0 to 5 liter/m² filtered time and 50 to 55liter/m² filtered time is 3 or more can be regarded as an index showingthat persistency of the virus removal ability of the membrane issufficiently high.

Proteins in a plasma derivative or a biopharmaceutical are liable to beadsorbed to a hydrophobic membrane, in other words, they are hardlyadsorbed to a hydrophilic membrane, and the hydrophilicity of themembrane can be estimated by contact angle of water. There are twomethods for measuring contact angle, static contact angle method anddynamic contact angle method, and the dynamic contact angle method,which provides information on surface dynamics, is preferable. Among thedynamic contact angle methods, the measuring method according to theWilhelmy method with high flexibility of sample form is more preferable.

Among the contact angles of water, receding contact angle of waterserves as an important index for estimating the hydrophilicity of themembrane, since the receding contact angle directly reflects thehydrophilicity of the membrane surface in water. The hydrophilicmicroporous membrane of the present invention preferably has a recedingcontact angle of water of 0 to 20 degrees, more preferably 0 to 15degrees, still more preferably 0 to 10 degrees and most preferably 0 to5 degrees. When the receding contact angle of water exceeds 20 degrees,the hydrophilicity of the membrane is insufficient and a rapid fall ofthe filtration rate will be caused by adsorption of protein.

Although the form of hydrophilic microporous membrane of the presentinvention is applicable in any form including a flat membrane, a hollowfiber, etc., hollow fiber is preferable from the viewpoint of easinessof production.

The membrane thickness of hydrophilic microporous membrane of thepresent invention is preferably 15 μm to 1000 μm, more preferably 15 μmto 500 μm, and most preferably 20 μm to 100 μm. When the membranethickness is 15 μm or more, not only strength of the microporousmembrane is sufficient but also certainty in virus removal issufficient. Membrane thickness exceeding 1000 μm is not preferable sincethe permeation capability tends to fall.

The porosity of hydrophilic microporous membrane in the presentinvention is 20 to 90%, preferably 30 to 85%, and more preferably 40 to80%. When the porosity is less than 20%, filtration rate is not enoughand when the porosity exceeds 90%, there is a tendency that thecertainty of virus removal decreases and the strength of microporousmembrane becomes insufficient and therefore it is not preferable.

Although water permeativity of the hydrophilic microporous membrane ofthe present invention varies depending on the pore size, it ispreferably 2×10⁻¹¹ to 3×10⁻⁸, more preferably 4×10⁻¹¹ to 1.5×10⁻⁸, mostpreferably 5×10⁻¹¹ to 8.5×10⁻⁹. The unit of the water permeativity ism³/m²/second/Pa. When the water permeativity is 2×10⁻¹¹ or more, waterpermeativity sufficient for use as a separation membrane can be obtainedand therefore it is preferable. On the other hand, in consideration ofkeeping the strength of hydrophilic microporous membrane or securing thecertainty of virus removal, water permeativity exceeding 3×10⁻⁸ is notrealistic.

The surface of the hydrophilic microporous membrane of the presentinvention and the surface of the micropores preferably show lowadsorptivity for proteins such as globulin. The degree of adsorptivitycan be evaluated by permeating a diluted solution of globulin which is atypical plasma protein, and quantifying the proteins contained in theunfiltered solution and the filtrate by absorption spectrometer. Theamount of adsorption per 1 g of membrane when a bovine immunoglobulinsolution diluted to 100 mass ppm is made to permeate is 3 mg or less,more preferably 2 mg or less, and most preferably 1 mg or less.

As for the hydrophilic microporous membrane of the present invention, itis preferable that the maximum pore size is 10 to 100 nm and thestructure of the microporous membrane is not limited as long as itsatisfies the following formula (1) and formula (2). It is preferable,however, that the microporous membrane has a coarse structure layer witha higher open pore ratio and a fine structure layer with a lower openpore ratio, and the above-described coarse structure layer exists on atleast one side of the membrane surface and has a thickness of 2 μm ormore and the thickness of the above-described fine structure layer is50% or more of the whole membrane thickness, and the above-describedcoarse structure layer and the above-described fine structure layer areformed in one piece. This is because such a structure facilitates tosecure the initial filtration rate satisfying the formula (1) and tokeep the filtration rate satisfying the formula (2).Globulin permeation rate A>0.0015×maximum pore size (nm)^(2.75)   (1)Globulin permeation rate B/globulin permeation rate A>0.2   (2).

Microporous membranes having a preferable structure will be describedbelow.

In the above-described microporous membrane, the coarse structure layerpreferably exists on at least one side of the membrane surface and thethickness of the coarse structure layer is preferably 2 μm or more, morepreferably 3 μm or more, still more preferably 5 μm or more andparticularly preferably 8 μm or more. The coarse structure layer has apre-filter function, and alleviates decrease in the filtration rate dueto the blockade by impurities. As the pore size of microporous membraneis smaller, impurities contained in physiologically active substancesmay more readily cause decrease in the filtration rate, and thus thethickness of the coarse structure layer is preferably large.

In the meantime, the thickness of the fine structure layer is preferably50% or more of the whole membrane thickness. When the thickness of thefine structure layer is 50% or more of the whole membrane thickness, itcan be used without reducing removing performance such as for viruses.It is more preferably 55% or more, and particularly preferably 60% ormore.

The above-described coarse structure layer is a part where open poreratio is relatively large in the whole membrane thickness and improvesprocessing performance of the membrane by exhibiting a pre-filterfunction on the suspending substances contained in a protein solution orthe like. On the other hand, the above-described fine structure layer isa part where open pore ratio is relatively small in the whole membranethickness and substantially defines the membrane pore size. It is thelayer which has the function of removing particles in a microporousmembrane to remove particles such as viruses.

Both of the porosity and the open pore ratio respectively correspond tothe capacity ratio of the pored portion in the microporous membrane ofthe present invention and they are the same in the basic concept but theporosity is a numerical value obtained from an apparent volumecalculated from the cross-sectional area across the membrane and thelength and the mass of the membrane and the true density of the membranematerial, whereas the open pore ratio is an area ratio of the poredportions to the cross-sectional area of the membrane in thecross-section of the membrane, which can be determined from the imageanalysis of the electron microscope photograph of the cross-section ofthe membrane. In the present invention, open pore ratio is measured forevery predetermined thickness in the membrane thickness direction inorder to investigate changes in the capacity ratio of the pored portionsin the membrane thickness direction, and it is measured for every 1 μmthickness in consideration of measurement accuracy.

Specifically, the open pore ratio is an average open pore ratiodetermined by dividing observation result of the cross-sectionalstructure in the direction perpendicular to the membrane surface of themicroporous membrane for every 1 μm thickness in the thicknessdirection, determining the open pore ratio by image-processing analysisfor each of the divided regions and averaging these open pore ratios fora predetermined membrane thickness region, and the average open poreratio of the whole membrane thickness is a open pore ratio which isdetermined by averaging the open pore ratios obtained for each of thedivided regions throughout the whole membrane thickness.

In the present invention, the coarse structure layer is a layer with ahigher open pore ratio which exists adjacent to the membrane surface,and preferably it is a layer in which (A) open pore ratio is the averageopen pore ratio of the whole membrane thickness+2.0% or more(hereinafter referred to as the coarse structure layer of (A)), morepreferably+2.5% or more of layer, particularly preferably+3.0% or more.The upper limit of the open pore ratio of the coarse structure layer ispreferably the average open pore ratio of the whole membranethickness+30% or less, more preferably the average open pore ratio ofthe whole membrane thickness+25% or less, particularly preferably theaverage open pore ratio of the whole membrane thickness+20% or less.When the open pore ratio of the coarse structure layer is the averageopen pore ratio of the whole membrane thickness+2.0% or more, thestructural difference from the fine structure layer is also sufficientlylarge, which allows to exhibit pre-filtering effect and provides aneffect of increasing the processing performance of the microporousmembrane. On the other hand, when the open pore ratio of the coarsestructure layer is more than the average open pore ratio of the wholemembrane thickness+30%, the structure of the coarse structure layer isunnecessarily coarse and may have only insufficient pre-filter functionand therefore it is not preferable.

Furthermore, the coarse structure layer preferably has a gradientstructure where the open pore ratio decreases continuously from themembrane surface to the fine structure layer. The reason why this ispreferable is that the pore size decreases continuously as the open poreratio decreases continuously, thereby large suspending substances areremoved near the surface and smaller suspending substances are graduallyremoved as going deeper into the inside and thus the pre-filter functionof the coarse structure layer is improved. It is not preferable that theopen pore ratio changes a lot discontinuously on the boundary betweenthe coarse structure layer and the fine structure layer since thesuspending substances accumulate near the boundary and cause decrease inthe filtration rate. The gradient structure where the open pore ratiodecreases continuously as used herein means an overall tendency in themembrane thickness direction, and there may be some local inversions ofthe open pore ratio resulting from structural variation or measurementerrors.

The coarse structure layer preferably contains a layer where the openpore ratio is the average open pore ratio of the whole membranethickness+5.0% or more, and still more preferably contains a layer wherethe open pore ratio is the average open pore ratio of the whole membranethickness+8.0% or more. When the coarse structure layer contains a layerwhere the open pore ratio is the average open pore ratio of the wholemembrane thickness+5.0% or more, it means that the coarse structurelayer has a layer having a sufficiently larger pore size than the finestructure layer, the coarse structure layer can exhibit sufficientpre-filter function. The layer which has the maximum open pore ratio ispreferably present on the membrane surface or near the membrane surface.

In addition, the average pore size on the surface of the membrane towhich the coarse structure layer is adjacent in the microporous membraneis preferably twice more the maximum pore size determined by the bubblepoint method, and more preferably three times more the maximum pore sizedetermined by the bubble point method. If the average pore size on thesurface of the membrane to which the coarse structure layer is adjacentis below twice the maximum pore size determined by the bubble pointmethod, the pore size is too small and there is a tendency thatsuspending substances deposit on the surface to cause decrease in thefiltration rate, which is not preferable. When the microporous membraneis used for removing particles such as viruses, the average pore size onthe surface of the membrane to which the coarse structure layer isadjacent is preferably 3 μm or less, more preferably 2 μm or less. Ifthe above-described average pore size exceeds 3 μm, there is a tendencythat the pre-filter function deteriorates, which is not preferable.

The fine structure layer is a layer with a lower open pore ratio, andpreferably it is a layer in which (B) open pore ratio is less than theaverage open pore ratio of the whole membrane thickness+2.0% and in therange of (the average value of the open pore ratio of the layer in whichthe open pore ratio is less than the average open pore ratio of thewhole membrane thickness+2.0%)±2.0% (including both the ends)(hereinafter referred to as the fine structure layer of (B)). The factthat the open pore ratio of the fine structure layer is in the range of(the average value of the open pore ratio of the layer in which the openpore ratio is less than the average open pore ratio of the wholemembrane thickness+2.0%)±2.0% (including both the ends) means that thefine structure layer has a relatively homogeneous structure, and this isimportant for removing a virus or the like by depth filtration. Thehigher the homogeneity of the fine structure layer, the more preferable,and the range of variation of the open pore ratio is preferably withinthe range of ±2%, still more preferably within the range of ±1%. As anexample of structure of the fine structure layer, the void structure inspherocrystal disclosed in the International Publication WO01/28667pamphlet can be preferably applied.

An intermediate region belonging to neither the above-described coarsestructure layer of (A) nor the fine structure layer of (B) may alsoexist in the microporous membrane. The intermediate region as usedherein corresponds to a layer where the open pore ratio is less than theaverage open pore ratio of the whole membrane thickness+2.0% but doesnot fall in the range of (the average value of the open pore ratio ofthe layer in which the open pore ratio is less than the average openpore ratio of the whole membrane thickness+2.0%)±2.0% (including boththe ends). Such a layer usually exists in the boundary portions betweenthe coarse structure layer of (A) and the fine structure layer of (B).

As for the microporous membrane, it is preferable that the coarsestructure layer and the fine structure layer are formed in one piece.The expression that the coarse structure layer and the fine structurelayer are formed in one piece means that the coarse structure layer andthe fine structure layer are simultaneously formed at the time ofproduction of the microporous membrane. Under the present circumstances,an intermediate region may exist in the boundary portions between thecoarse structure layer and the fine structure layer. As compared to amembrane produced by coating a comparatively small pore sized layer onthe large pore sized support or a laminated membrane comprisinglaminated membranes having different pore sizes, it is more preferablethat the coarse structure layer and the fine structure layer are formedin one piece. The membrane produced by coating and the laminatedmembrane comprising laminated membranes having different pore sizes, inwhich the connectivity of the pores becomes low or the pore size changesdiscontinuously a lot between two layers, have defects that suspendingsubstances tend to deposit between the support and the coating layer.

The process for producing a hydrophilic microporous membrane of thepresent invention will be described below.

The thermoplastic resin used for producing a microporous membrane of thepresent invention is a thermoplastic resin having crystallizingproperties which is used for usual compression, extrusion, ejection,inflation and blow moldings and polyolefin resins such as polyethyleneresin, polypropylene resin and poly 4-methyl-1-pentene resin; polyesterresins such as polyethylene terephthalate resin, polybutyleneterephthalate resin, polyethylene terenaphthalate resin, polybutylenenaphthalate resin, polycyclohexylenedimethylene terephthalate resin;polyamide resins such as nylon 6, nylon 66, nylon 610, nylon 612, nylon11, nylon 12, and nylon 46; fluoride resins such as polyvinylidenefluoride resin, ethylene/tetrafluoroethylene resin andpolychlorotrifluoroethylene resin; polyphenylene ether resins; andpolyacetal resins, etc. can be used.

Among the above-described thermoplastic resins, polyolefin resins andfluoride resins have good balance of heat resistance and moldingprocessability and therefore they are preferable, and inter aliapolyvinylidene fluoride resins are particularly preferable. Thepolyvinylidene fluoride resin as used herein refers to a fluoride resincontaining vinylidene fluoride units as a backbone structure, and isgenerally referred to by the abbreviated name of PVDF. As such apolyvinylidene fluoride resin, a homopolymer of vinylidene fluoride(VDF), a copolymer of one or two monomers selected from the monomergroup consisting of hexafluoropropylene (HFP), pentafluoropropylene(PFP), tetrafluoroethylene (TFE), chlorotrifluoroethylene (CTFE) andperfluoromethyl vinyl ether (PFMVE) with vinylidene fluoride (VDF) canbe used. The above-described homopolymer and the above-describedcopolymer can also be mixed and used. In the present invention,polyvinylidene fluoride resin containing 30 to 100 wt % of a homopolymeris preferably used since the crystallinity of the microporous membranewill be improved and the strength thereof will become high, and it isstill more preferable to use only homopolymer.

The average molecular weight of the thermoplastic resin used in thepresent invention is preferably 50,000 to 5,000,000, more preferably100,000 to 2,000,000, still more preferably 150,000 to 1,000,000.Although this average molecular weight indicates weight averagemolecular weight obtained by gel permeation chromatography (GPC)measurement, since correct GPC measurement is generally difficult for aresin having an average molecular weight exceeding 1,000,000, viscosityaverage molecular weight by the viscosity method can be adopted insteadthereof. If the weight average molecular weight is smaller than 50,000,the melt tension during melt molding becomes small, with the result thatshapability will be deteriorated or the membranous mechanical strengthwill become low, and therefore it is not preferable. If the weightaverage molecular weight exceeds 5,000,000, uniform melt-blendingbecomes difficult, and therefore it is not preferable.

The polymer concentration of the thermoplastic resin used in the presentinvention is preferably 20 to 90 wt %, more preferably 30 to 80 wt %,and most preferably 35 to 70 wt % in the composition containing athermoplastic resin and a plasticizer. If the polymer concentrationbecomes less than 20 wt %, problems will occur, for example, membraneforming properties are deteriorated and sufficient mechanical strengthcannot be obtained. In addition, pore size of the microporous membraneobtained becomes too large as a membrane for removing viruses, and thevirus removal performance becomes insufficient. If the polymerconcentration exceeds 90 wt %, the porosity becomes small while the poresize of microporous membrane obtained becomes too small, and thereforethe filtration rate decreases and the membrane cannot be usedpractically.

As a plasticizer used in the present invention, a non-volatile solventwhich can form a uniform solution at a temperature not less than themelting point of the crystal of a thermoplastic resin when theplasticizer is mixed with the thermoplastic resin with a composition forproducing a microporous membrane is used. The non-volatile solvent herehas a boiling point of 250° C. or more under atmospheric pressure. Theform of a plasticizer may be a liquid or a solid generally at a normaltemperature of 20° C. It is preferable to use a plasticizer of so-calledsolid-liquid phase separation system for producing a membrane which hasa small pore sized and homogeneous fine structure layer to be used forvirus removal, which plasticizer has a thermally induced solid-liquidphase separation point at a temperature not lower than normaltemperature when a uniform solution with thermoplastic resin is cooled.Some plasticizers have a thermally induced liquid-liquid phaseseparation point at a temperature not lower than normal temperature whena uniform solution with a thermoplastic resin is cooled but generallythe use of a plasticizer of liquid-liquid phase separation system tendsto form obtained microporous membrane in large pore sizes. Theplasticizer used here may be a single substance or a mixture of two ormore substances.

The method for measuring a thermally induced solid-liquid phaseseparation point may comprise using as a sample a composition containinga thermoplastic resin and a plasticizer of the predeterminedconcentration and melt-blended beforehand, and measuring the exothermicpeak temperature of this resin by thermal analysis (DSC). The method ofmeasuring the crystallizing point of this resin may also comprise usingas a sample the resin melt-blended beforehand, and conducting thermalanalysis in a similar manner.

As a plasticizer used preferably for the production of a membrane whichhas a small pore sized and homogeneous fine structure layer and is usedfor virus removal, a plasticizer disclosed in International PublicationWO01/28667 pamphlet can be mentioned. That is, a plasticizer for which adepression constant of the phase separation point of the compositiondefined by the following formula is 0 to 40° C., preferably 1 to 35° C.,still more preferably 5 to 30° C. can be mentioned. If the depressionconstant of the phase separation point exceeds 40° C., homogeneity ofthe pore size and strength are deteriorated and therefore such aplasticizer is not preferable.α=100×(T _(c) ⁰ −T _(c))/(100−C)wherein α represents a depression constant of the phase separation point(° C.), T_(c) ⁰ represents a crystallizing temperature (° C.) of thethermoplastic resin, T_(c) represents a thermally induced solid-liquidphase separation point (° C.) of the composition and C represents aconcentration (wt %) of the thermoplastic resin in the composition.

For example, when polyvinylidene fluoride resin is selected as athermoplastic resin, dicyclohexyl phthalate (DCHP), diamylphthalate(DAP), triphenyl phosphate (TPP), diphenylcresyl phosphate(CDP), tricresyl phosphate (TCP), etc. are particularly preferable.

In the present invention, the first method for carrying out uniformdissolution of the composition containing a thermoplastic resin and aplasticizer is a method comprising feeding the resin into a continuousresin blending machine such as an extruder, introducing a plasticizer inan arbitrary ratio while heat melting the resin and carrying out screwblending to obtain a uniform solution. The form of the resin to be fedmay be in any shape of a powder, a granule and a pellet. When carryingout the uniform dissolution by this method, the form of the plasticizeris preferably a liquid at a normal temperature. As an extruder, a singleaxis screw extruder, two-axis opposite direction screw extruder,two-axis same direction screw extruder, etc. can be used.

The second method of carrying out uniform dissolution of the compositioncontaining a thermoplastic resin and a plasticizer is a methodcomprising mixing and dispersing a plasticizer in a resin beforehandusing a churning equipment such as a Henschel mixer and feeding theresultant composition into a continuous resin blending machine such asan extruder and carrying out melt-blending to obtain a uniform solution.The form of the composition to be fed may be in a shape of slurry whenthe plasticizer is a liquid at normal temperature, and in a shape of apowder, a granule or the like when the plasticizer is a solid at normaltemperature.

The third method of carrying out uniform dissolution of the compositioncontaining a thermoplastic resin and a plasticizer is a method of usinga simple form resin blending machine such as a brabender and a mill, anda method of melt-blending within a blending container of the other batchtype. According to these methods, it cannot be said that productivity isgood since they are batch type processes, but there is an advantage thatthey are simple and highly flexible.

In the present invention, after the composition containing athermoplastic resin and a plasticizer is heated to a temperature notlower than the melting point of the crystal of the thermoplastic resinto form a uniform solution, the composition is extruded in the form of aflat membrane or a hollow fiber from a discharging orifice such as aT-die, a circular die and an annular spinneret, and cooled tosolidification to shape a membrane form (step (a)). In the step (a) inwhich the composition is cooled to solidification to shape a membraneform, the fine structure layer is formed while the coarse structurelayer is formed adjacent to the membrane surface.

In the present invention, the composition containing a thermoplasticresin and a plasticizer which is heated and uniformly dissolved isdischarged from a discharging orifice and the membrane is taken over ata taking-over rate so that the draft ratio defined below may be not lessthan 1 and not more than 12, while a non-volatile liquid heated to 100°C. or more which is capable of partially solubilizing the thermoplasticresin is contacted with one membrane surface and the other side of themembrane is cooled to form a coarse structure layer and a fine structurelayer.Draft ratio=(membrane taking-over rate)/(discharging rate of thecomposition at the discharging orifice)

The above-described draft ratio is preferably not less than 1.5 and notmore than 9, more preferably not less than 1.5 and not more than 7. Ifthe draft ratio is less than 1, no tension is loaded on the membrane andthe shapability is poor and if it exceeds 12, the membrane is extendedand therefore it is difficult to form a coarse structure layer having asufficient thickness. The discharging rate of the composition at thedischarging orifice as used herein is given by the following formula:Discharging rate of the composition at the discharging orifice=(volumeof composition discharged per unit time)/(area of discharging orifice)

The preferable range of the discharging rate is 1 to 60 m/min, morepreferably 3 to 40 m/min. When the discharging rate is less than 1m/min, problems occur such as increase in fluctuation of the dischargingvolume in addition to decrease in productivity. On the contrary, if thedischarging rate exceeds 60 m/min, since there is much dischargingvolume, a turbulent flow may occur at the discharging orifice, and thedischarging state may become unstable.

Although the taking-over rate can be set according to the dischargingrate, it is preferably 1 to 200 m/min, more preferably 3 to 150 m/min.If the taking-over rate is less than 1 m/min, productivity andshapability are deteriorated, and if the taking-over rate exceeds 200m/min, cooling time becomes short, tension loaded on the membraneincreases and accordingly rupture of the membrane tends to occur.

A preferable method of forming a coarse structure layer is a method inwhich one side of the surfaces of uncured membrane formed by extrudingthe composition containing a thermoplastic resin and a plasticizer fromthe extruding orifice into a membrane of the shape of a flat membrane ora hollow fiber is contacted with a non-volatile liquid which is capableof partially solubilizing the thermoplastic resin. In this case, acoarse structure layer is formed by diffusion of the contacted liquidinside the membrane and a partial dissolution of the thermoplasticresin. The liquid which is capable of partially solubilizing thethermoplastic resin as used herein is a liquid which cannot form auniform solution unless the temperature is elevated to 100° C. or morewhen it is mixed with the thermoplastic resin in 50 wt % concentration,and preferably it is a liquid which can form a uniform solution at atemperature not lower than 100° C. and not higher than 250° C., and morepreferably it is a liquid which can form a uniform solution at atemperature not lower than 120° C. and not higher than 200° C. If theliquid which can achieve uniform dissolution at a temperature lower than100° C. is used as a contact liquid, cooling solidification of thecomposition solution containing a thermoplastic resin and a plasticizeris prevented, and consequently problems may occur, for example,shapability may be deteriorated, the coarse structure layer may becomeunnecessarily thick, or the pore size becomes excessively large. In thecase of the liquid which cannot form a uniform solution at a temperaturelower than 250° C., the solubility of the thermoplastic resin is toolow, and it is difficult to form a coarse structure layer having asufficient thickness. The non-volatile liquid as used herein is a liquidhaving a boiling point exceeding 250° C. under 101325 Pa.

For example, when polyvinylidene fluoride resin is selected as athermoplastic resin, phthalic acid esters, adipic acid esters andsebacic acid esters in which the carbon chain length of the ester chainis seven or less, phosphoric acid esters and citric acid esters in whichthe carbon chain length of the ester chain is eight or less can bepreferably used, and particularly, diheptyl phthalate, dibutylphthalate, diethyl phthalate, dimethyl phthalate, dibutyl adipate,dibutyl sebacate, tri(2-ethylhexyl) phosphate, tributyl phosphate,acetyltributyl citrate, etc. can be used suitably.

However, plasticizers having an annular structure such as a phenylgroup, a cresyl group, a cyclohexyl group, etc. in the ester chain,i.e., dicyclohexyl phthalate, (DCHP), diamyl phthalate(DAP), triphenylphosphate (TPP), diphenylcresyl phosphate (CDP), tricresyl phosphate(TCP), etc. do have exceptionally poor capability to form a coarsestructure layer and they are not preferable.

The temperature of the contacting liquid used to introduce a coarsestructure layer is a temperature not lower than 100° C., preferably notlower than 120° C., and not higher than the temperature of the uniformsolution of a thermoplastic resin and a plasticizer, still morepreferably a temperature not lower than 130° C., and not higher than(the temperature of the uniform solution of a thermoplastic resin and aplasticizer—10° C.). If the temperature of the contacting liquid islower than 100° C., the solubility of the thermoplastic resin is toolow, and therefore it tends to be difficult to form a coarse structurelayer having a sufficient thickness. If the temperature exceeds thetemperature of the uniform solution of the thermoplastic resin and theplasticizer, shapability is deteriorated.

When a coarse structure layer is introduced only on one side of themicroporous membrane, the cooling method of the surface of the otherside corresponding to the fine structure layer side can follow anyconventional method. That is, it can be carried out by contacting a heatconducting object to effect cooling. As the heat conducting object,metal, water, air, or the plasticizer itself can be used. Specifically,a method of introducing a coarse structure layer is possible whichcomprises extruding a uniform solution containing a thermoplastic resinand a plasticizer in the shape of a sheet through a T-die etc., carryingout contact cooling with a metal roll, and bringing the other side ofthe membrane which does not contact with the roll into contact with anon-volatile liquid which is capable of partially solubilizing thethermoplastic resin. Alternatively a method is possible which comprisesextruding a uniform solution containing a thermoplastic resin and aplasticizer in the shape of a cylinder or a hollow fiber through acircular die, annular spinneret, etc., and passing a non-volatile liquidwhich is capable of partially solubilizing the thermoplastic resinthrough inside the cylinder or hollow fiber to form a coarse structurelayer in the inner surface side while contacting the outside with acooling media such as water to effect cooling.

When the coarse structure layer is introduced on both the sides of themicroporous membrane, a uniform solution containing a thermoplasticresin and a plasticizer is extruded in a predetermined shape through aT-die, a circular die, annular spinneret, etc., a circular die, annularspinneret, and the solution is contacted with a non-volatile liquidwhich is capable of partially solubilizing the thermoplastic resin onboth the sides to form a coarse structure layer, which is then cooled tosolidification. Cooling method in this process can follow anyconventional method. When the time after contacting the non-volatileliquid which is capable of partially solubilizing the thermoplasticresin until the cooling starts is too long, problems may occur, forexample, shapability may be deteriorated, the strength of the membraneis deteriorated, etc., and therefore the time period after contactingthe contacting liquid till the start of the cooling is preferably 30seconds or less, more preferably 20 seconds or less, and particularlypreferably 10 seconds or less.

In the production method of the microporous membrane of the presentinvention, in order to form a small pore sized and homogeneous finestructure layer, it is preferable to make the cooling rate at the timeof effecting cooling solidification sufficiently high. The cooling rateis preferably 50° C./min or more, more preferably 100 to 1×10⁵° C./min,still more preferably 200 to 2×10⁴° C./min. Specifically, the method ofcontacting with a metal cooling roll and water is preferably used, andparticularly, the method of contacting with water is preferable since itcan attain rapid cooling by evaporation of water.

In the step (b) which removes the substantial portion of theplasticizer, in order to remove a plasticizer, an extracting solvent isused. It is preferable that the extracting solvent is a poor solvent forthe thermoplastic resin and is a good solvent for the plasticizer, andthe boiling point thereof is lower than the melting point of microporousmembrane. Examples of such an extracting solvent include hydrocarbonssuch as hexane and cyclohexane; halogenated hydrocarbons such asmethylene chloride and 1,1,1-trichloroethane; alcohols such as ethanoland isopropanol; ethers such as diethyl ether and tetrahydrofuran;ketones such as acetone and 2-butanone; or water.

In the present invention, the first method of removing a plasticizer isperformed by immersing and fully washing the microporous membrane cutoff in the predetermined size in a container containing an extractingsolvent and making the adhering solvent air-dried or dried by hot air.Under the present circumstances, the immersing and washing operationsare preferably repeated many times since the plasticizer remaining inthe microporous membrane will decrease accordingly. It is preferable toconstrain the ends of the microporous membrane, which suppressescontraction of the microporous membrane during a series of operations ofimmersion, washing and drying.

The second method of removing a plasticizer comprises continuouslyfeeding the microporous membrane into a bath filled with an extractingsolvent, immersing the membrane in the tub over sufficient time toremove a plasticizer, and then drying the solvent adhered to themembrane. Under the present circumstances, it is preferable to applywell-known techniques such as a multi-stage method in which the insideof the tub is divided into plural stages and the microporous membranesare fed one by one into each tub having different concentrations, or acounter-flow method in which the extracting solvent is supplied in thedirection opposite to the running direction of the microporous membrane,and thereby a concentration gradation is provided, in order to enhanceextraction efficiency. It is important that a plasticizer is removedfrom the microporous membrane substantially in either of the first andsecond methods. Removing substantially means that the plasticizer in themicroporous membrane is removed to an extent which does not spoil theperformance as a separation membrane and the amount of the plasticizerremaining in the microporous membrane is preferably 1 wt % or less, morepreferably 100 mass ppm or less. The quantification of the amount of theplasticizer which remains in the microporous membrane can be carried outby gas chromatography, liquid chromatography, etc. It is furtherpreferable to raise the temperature of the extracting solvent to atemperature lower than the boiling point of the solvent, preferably inthe range of not higher than (the boiling point —5° C.), since thediffusion of the plasticizer and the solvent can be promoted, and theextraction efficiency is improved.

In the present invention, the microporous membrane may be heat-treatedbefore, or after, or both before and after the step for removing aplasticizer, which provides effects such as reduction of contraction ofthe microporous membrane at the time of removing a plasticizer,improvement in the strength and improvement in heat resistance of themicroporous membrane. There are some methods of performingheat-treatment such as a method of disposing the microporous membrane ina hot air, a method of immersing the microporous membrane in a heatmedium, or a method of contacting the microporous membrane with a metalroll which has been heated and heat-controlled. When the size is fixedand the membrane is heat-treated, particularly, blockades of minuteholes can be prevented and therefore such a method is preferable.

Although the temperature of heat-treatment varies depending on thepurpose and the melting point of the thermoplastic resin, in the case ofthe vinylidene fluoride membrane used for a virus removal, 121 to 175°C. is preferable, more preferably 125 to 170° C. The temperature 121° C.is used by general high-pressure steamy sterilization, and thecontraction and modification during high-pressure steamy sterilizationcan be prevented if heat-treatment is conducted at this temperature orhigher. If the temperature exceeds 175° C., which is close to themelting point of vinylidene fluoride, disadvantages may occur, forexample, the membrane may be ruptured or minute pores may be closedduring the heat-treatment.

The microporous membrane which consists of a hydrophobic resin excellentin physical strength is excellent in that it can be endured against highfiltration pressure as compared with a microporous membrane whichconsists of hydrophilic resin such as cellulose while the former tendsto cause adsorption of a protein or the like, contamination and cloggingof the membrane, etc., resulting in a rapid fall of filtration rate.Therefore, when a microporous membrane which consists of a hydrophobicresin is used, it is preferable to impart the membrane withhydrophilicity in order to prevent blockade due to the adsorption ofprotein, etc. In the production method of the present invention, it ispreferable to introduce a hydrophilic functional group into the surfaceof the pores of the hydrophobic membrane by graft polymerization method,and to reduce adsorptivity such as that of protein.

The graft polymerization method is a reaction in which radicals aregenerated on the polymer microporous membrane by means such as ionizingradiation and chemical reaction and a monomer is graft polymerized ontothe membrane using the radical as a starting point.

In the present invention, although any means can be adopted in order togenerate radicals on the polymer microporous membrane, but in order togenerate radicals uniformly over the whole membrane, irradiation ofionizing radiation is preferable. As a kind of ionizing radiation,γ-ray, electron beam, β-ray, neutron beam, etc. can be used, butelectron beam or γ-ray is most preferable in the implementation on anindustrial scale. Ionizing radiation can be obtained from radioactiveisotopes such as cobalt 60, strontium 90, and cesium 137, or by X-rayphotography equipment, electron beam accelerator, ultraviolet rayirradiation equipment, etc.

The irradiation dose of the ionizing radiation is preferably not lessthan 1 kGy and not more than 1000 kGy, more preferably not less than 2kGy and not more than 500 kGy, most preferably not less than 5 kGy andnot more than 200 kGy. Radicals are not generated uniformly below 1 kGywhile the strength of the membrane may be deteriorated over 1000 kGy.

The graft polymerization method by irradiation of ionizing radiation isgenerally roughly divided into a pre-irradiation method in whichradicals are generated in the membrane and subsequently the membrane iscontacted to the reactant compounds and a simultaneous irradiationmethod in which radicals are generated in the membrane while themembrane is contacted to the reactant compounds. In the presentinvention, any method can be applied, but the pre-irradiation method ispreferable since it generates less amount of oligomers.

A hydrophilic vinyl monomer which has one vinyl group as a reactantcompound, and a cross-linking agent used if needed are made to contactwith a polymer microporous membrane in which radicals have beengenerated in the present invention. Although the method of carrying outcontact can be performed also either on a gaseous phase or a liquidphase, the method of carrying out contact in a liquid phase in which agraft reaction progresses uniformly is preferable. For the purpose ofmaking the graft reaction still more uniformly, it is preferable that ahydrophilic vinyl monomer which has one vinyl group or a hydrophilicvinyl monomer and a cross-linking agent when a cross-linking agent isused are dissolved in a solvent beforehand and then the contact with apolymer microporous membrane is carried out.

As described above, the hydrophilic microporous membrane of the presentinvention comprises a polymer microporous membrane on which ahydrophilic vinyl monomer having one vinyl group is graft polymerized toimpart the surface of the micropores with hydrophilicity therebyreducing adsorption of physiologically active substances such asprotein. The hydrophilic vinyl monomer which has one vinyl group in thepresent invention is a monomer which has one vinyl group and uniformlydissolves in a pure water of 25° C. when mixed therein at 1 vol % underatmospheric pressure. Examples of the hydrophilic vinyl monomer includevinyl monomers having a hydroxyl group or a functional group used as aprecursor thereof such as hydroxypropyl acrylate, hydroxybutyl acrylate;vinyl monomers having an amide bond such as vinyl pyrrolidone; vinylmonomers having an amino group such as acrylics amide; vinyl monomershaving a polyethyleneglycol chain such as polyethyleneglycolmonoacrylate; vinyl monomers having an anion exchange groups such astriethylammoniumethyl methacrylate; vinyl monomers having a cationexchange groups such as sulfopropyl methacrylate,

In the present invention, among the hydrophilic vinyl monomers, theabove-described hydrophilic vinyl monomer which has one or more hydroxylgroup or a functional group used as a precursor thereof is preferablyused since the use thereof reduces a receding contact angle of themembrane. More preferably, esters of acrylic acid or methacrylic acidand a polyhydric alcohol such as hydroxypropyl acrylate and2-hydroxyethyl methacrylate; alcohols having an unsaturated bond such asallyl alcohol; and enol esters such as vinyl acetate and vinylpropionate are used and most preferably esters of acrylic acid ormethacrylic acid and a polyhydric alcohol such as hydroxypropyl acrylateand 2-hydroxyethyl methacrylate are used. The hydrophilic microporousmembrane to which hydroxypropyl acrylate is grafted has a low recedingcontact angle and provides a sufficient globulin permeating ability.

A vinyl monomer which has two or more vinyl groups has a tendency toperform cross-linking in the hydrophilic diffusive layer throughcopolymerization and reduce the permeability of protein even if it ishydrophilic, and accordingly it is not preferable from the viewpoint ofprotein permeativity, but it is possible to use such a monomer if neededas a cross-linking agent since it has an effect of preventing adherencebetween membranes and reducing dissolution-out from the membrane.

The vinyl monomer which has two or more vinyl groups used as across-linking agent is advantageous when the receding contact angle islower taking into consideration the adsorptivity of the microporesurfaces for protein and therefore it is preferable to use a hydrophiliccross-linking agent. The hydrophilic cross-linking agent is a monomerwhich has two or more vinyl groups and uniformly dissolves in a purewater of 25° C. when mixed therein at 1 vol % under atmosphericpressure.

When such a cross-linking agent, i.e., vinyl monomer which has two ormore vinyl groups is used, it is copolymerized at a proportion to thehydrophilic vinyl monomer which has one vinyl group of preferably 10mol% or less, more preferably 0.01 to 10 mol %, further preferably 0.01to 7 mol % and most preferably 0.01 to 5 mol %. The permeability ofprotein is not enough if it exceeds 10 mol %.

The cross-linking agent used in the present invention has preferably anumber average molecular weight of 200 or more and 2000 or less, morepreferably a number average molecular weight of 250 or more and 1000 orless, most preferably a number average molecular weight of 300 or moreand 600 or less. It is preferable from the viewpoint of the filtrationrate of a protein solution that the number average molecular weight ofthe cross-linking agent is 200 or more and 2000 or less.

Specific examples of the cross-linking agent used in the presentinvention, i.e., the vinyl monomer which has two or more vinyl groups,include, for example, ethylene glycol dimethacrylate, polyethyleneglycol dimethacrylate, ethylene glycol diacrylate, polyethylene glycoldiacrylate, etc., and as other vinyl monomer which has two or more vinylgroups, cross-linking agents having three reactive groups such asdivinylbenzene derivatives and trimethylolpropane trimethacrylate canalso be used. Although these cross-linking agents can also be used as amixture of two or more kinds of compounds, it is preferable that theyare hydrophilic. Polyethylene glycol diacrylate is particularlypreferable from the viewpoint of the receding contact angle or proteinpermeativity.

A solvent which dissolves the hydrophilic vinyl monomer which has onevinyl group, and the cross-linking agent used if needed is notparticularly limited as long as the uniform dissolution can be carriedout. Examples of such a solvent include alcohols such as ethanol, andisopropanol, t-butyl alcohol; ethers such as diethyl ether andtetrahydrofuran; and ketones such as acetone and 2-butanone; water or amixture thereof.

The concentration of a hydrophilic vinyl monomer which has one vinylgroup, and the cross-linking agent used if needed at the time ofdissolving them is preferably from 3 vol % to 30 vol %, more preferablyfrom 3 vol % to 20 vol %, most preferably from 3 vol % to 15 vol %. Whenit is a concentration not less than 3 vol %, sufficient hydrophilicitycan be obtained and such a concentration is preferable. If it exceeds 30vol %, the micropores may be filled with the hydrophilized layer andthere is a tendency that permeation capability is deteriorated andtherefore such a concentration is not preferable.

The amount of the reaction liquid in which the hydrophilic vinyl monomerwhich has one vinyl group and the cross-linking agent used if needed aredissolved in a solvent used at the time of graft polymerization ispreferably 1×10⁻⁵ m³ to 1×10⁻³ m³ per 1 g of the polymer microporousmembrane. If the amount of the reaction liquid is 1×10⁻⁵ m³ to 1×10⁻³m³, membranes with enough homogeneity can be obtained.

The reaction temperature at the time of graft polymerization is notparticularly limited, although generally carried out at 20° C. to 80° C.

The present invention introduces the optimal hydrophilized layer to ahydrophobic microporous membrane, and realizes high proteinpermeativity. The ratio of the graft grafted to the hydrophobicmicroporous membrane for this purpose is preferably 3% or more and 50%or less, more preferably 4% or more and 40% or less, and most preferably6% or more and 30% or less. If the graft ratio is less than 3%,hydrophilicity of the membrane runs short and a rapid fall in thefiltration rate resulting from adsorption of protein is caused. If itexceeds 50%, relatively small pores will be filled with thehydrophilized layer and sufficient filtration rate cannot be obtained.The graft ratio as used herein is a value defined by the followingformula:Graft ratio (%)=100×((membrane mass after grafted−membrane mass beforegrafted)/membrane mass before grafted)

To the composition which constitutes the hydrophilic microporousmembrane of the present invention may be further blended, according tothe purpose, additives such as anti-oxidant, crystal core agent,antistatic agent, flame retardant, lubricant, and ultraviolet rayabsorbent if necessary.

The hydrophilic microporous membrane which has a heat resistance of thepresent invention can be used for a wide range of applications includinga separation membrane for medical use such as for removing,concentrating or as a culture medium of a virus, bacterium, etc., afilter for industrial processes which removes particles from apharmaceutical liquid or processed water, etc., a separation membranefor oil-water separation or liquid-gas separation, a separation membraneaiming at purification of city water and sewerage, and a separator forlithium ion battery, and a support for solid electrolyte polymerbatteries.

Hereafter, the present invention will be described in detail by way ofExamples but the present invention is not limited thereto. The testingmethods shown in Examples are as follows.

(1) Outer Diameter, Inner Diameter of Hollow Fiber, Thickness ofMembrane

The outer diameter, inner diameter of a hollow fiber is determined byphotographing the perpendicular section of the membrane at 210 timesmagnification using a substance microscope (SCOPEMAN503, product ofMoriteq Co., Ltd.). The thickness of the membrane was calculated as ½ ofthe difference of the outer diameter and the inner diameter of a hollowfiber.

(2) Porosity

The volume and mass of the microporous membrane were measured and thevoid ratio was calculated using the following formula from the obtainedresults.Porosity (%)=(1−mass/(density×volume of resin))×100(3) Water Permeativity

The volume of permeated pure water at 25° C. was measured byconstant-pressure dead-end filtration and the water permeativity wascalculated as the following formula from the area of the membrane,filtration pressure (0.1 MPa) and filtration time.Water permeativity (m³/m²/second/Pa)=permeation volume/(area ofmembrane×differential pressure×filtration time)(4) Maximum Pore Size

The bubble point (Pa) which can be determined by the bubble point methodbased on ASTM F 316-86 was converted to the maximum pore size (nm). As atesting liquid in which the membrane is immersed, a fluorocarbon liquidhaving a surface tension of 12 mN/m (Perfluorocarbon coolant FX-3250(trademark), product of Sumitomo 3M) was used. The bubble point wasdetermined by setting a hollow fiber having an effective length of 8 cmin a bubble point measurement equipment, gradually raising the pressureof the hollow side and reading the pressure when the gas flow ratepermeating the membrane reaches 2.4 E-3 liter/min.

(5) Structure Observation of Microporous Membrane

The microporous membrane cut off in a suitable size was fixed onto thesample stand with a conductive double-sided tape, and coated with goldto prepare a sample for microscopic observation. A high resolutionscanning electron microscope (HRSEM) (S-900, product of Hitachi, Ltd.)was used and structure observation of the surface and a section of themicroporous membrane was performed at an acceleration voltage of 5.0 kVand predetermined magnification.

(6) Open Pore Ratio and Average Open Pore Ratio

The open pore ratio was determined by dividing the observation result ofthe cross-sectional structure of the microporous membrane in thethickness direction for every 1 μm thickness, and obtaining as an arearatio of void to each divided region by image-processing analysis.Electron microscope photography at this time was performed at 15,000times magnification. The average open pore ratio is the average value ofopen pore ratio measured for the whole membrane thickness.

(7) Thickness of Coarse Structure Layer and Ratio of Fine StructureLayer to the Whole Thickness of Membrane

In the measurement of the above open pore ratio, it was judged whethereach divided region agreed with the definition of the fine structurelayer defined and the coarse structure layer as described. That is, thecoarse structure layer is a continuous region existing adjacent to themembrane surface and in which the open pore ratio measured in thethickness direction is higher by 2% or more than the average value ofthe open pore ratio for the whole membrane thickness, and the finestructure layer is a region other than the coarse structure layer and inwhich the open pore ratio measured in the thickness direction is withinthe range of less than ±2% of the average value of the open pore ratiofor the region excluding the coarse structure layer. The ratio of thefine structure layer to the whole thickness of membrane is a valueobtained by dividing the sum of the thicknesses of the agreeing regionsby the whole membrane thickness.

(8) Average Pore Size of the Coarse Structure Layer Side Surface

From the structure observation result of the coarse structure layer sidesurface, the number and area of pores which exist in the surface weremeasured by image-processing analysis, and a circle equivalent diameterof the pore was determined from the average area per pore assuming thatthe pore is a true circle. This circle equivalent diameter was regardedas the average pore size of the coarse structure layer side surface.Electron microscope (S-900, product of Hitachi, Ltd.) photography atthis time was performed at 6,000 times magnification.

(9) Measurement of Contact Angle on Membrane

The receding contact angle of the water on the membrane was measured byusing a water for injection (product of Otsuka Pharmaceutical Co., Ltd.;Japanese Pharmacopoeia) with the dynamic contact angle measuringinstrument (DCAT11, product of DataPhysics Instruments GmbH). A hollowfiber membrane was cut to about 2 cm, and mounted on the equipment. Thereceding contact angle was measured using the principle of the Wilhelmymethod. The motor speed at the time of measurement was 0.10 mm/second,the immersing depth was 10 mm, and 5-cycle measurement was carried outby regarding the advance and retreat as one cycle. The receding contactangle used was the average value of the value acquired by 5measurements.

(10) Amount of Adsorption of Bovine Immunoglobulin

The bovine immunoglobulin solution from Life Technology, Ltd. wasdiluted with a physiological saline solution (product of OtsukaPharmaceutical Co., Ltd.; Japanese Pharmacopoeia) to a concentration of0.01 wt %, and this was used as a source solution for filtration. Thesource solution for filtration was subjected to constant-pressuredead-end filtration under a filtration pressure of 0.3 MPa and afiltration temperature of 25° C., and the filtrate at 50 liter/m² fromthe start of filtration was sampled. Absorption at a wavelength of 280nm was measured for the source solution for filtration and the filtrate,and the amount of adsorption of bovine immunoglobulin was calculatedfrom the following formula.Amount of adsorption of bovine immunoglobulin (mg/g)=(absorption ofsource solution for filtration−absorption of filtrate)/absorption ofsource solution for filtration×0.005/membrane weight(11) Filtration Test of 3 wt % Bovine Immunoglobulin Solution

The bovine immunoglobulin solution from Life Technology, Ltd. wasdiluted with a physiological saline solution (product of OtsukaPharmaceutical Co., Ltd.; Japanese Pharmacopoeia) to a concentration of3 wt %, and this was pre-filtered further by the filtration membrane(product of Asahi Kasei Corporation, PLANOVA35N) for removing impuritiesand then used as a source solution for filtration. As a result ofmeasuring the molecular weight distribution of the bovine immunoglobulinin this source solution for filtration using liquid chromatography(product of TOSOH CORP., CCP&8020 series, product of AmershamBiosciences Company, Superdex by 200 HR 10/30), the ratio of polymer ofdimer or larger was not more than 20 wt %. Constant-pressure dead-endfiltration was performed for this source solution for filtration onconditions of a filtration pressure of 0.3 MPa and a filtrationtemperature of 25° C., and the permeation rate for 5 minutes after thestart of filtration and for 55 to 60 minutes after the start offiltration (liter/m²/h) was measured.

(12) Logarithmic Reduction Value of Porcine Parvovirus

As a source solution for filtration, supernatant of a culture solutionof ESK cell (pig kidney cell) cultured in a Dulbecco's MEMculture-medium solution (product of Nihon Biopharmaceutical ResearchInstitute) supplemented with 5% fetal bovine serum (product of Upstate,Ltd.) and infected with porcine parvovirus was used after pre-filteredby microporous membrane (product of Asahi Kasei Corporation,PLANOVA35N). Constant-pressure dead-end filtration was performed forthis source solution for filtration under the condition of a filtrationpressure of 0.3 MPa and a filtration temperature of 25° C. The filtratewas sampled as 11 fractions for every 5 ml (5 liter/m²), and in order tomeasure the logarithmic removing rate of porcine parvovirus at the timepoint by which 55 liter/m² has been filtered from the start offiltration, 1 ml was respectively sampled from each fraction and mixed.The concentration of the porcine parvovirus in the source solution forfiltration and the filtrate (the mixed solution and the first and thelast fractions) was determined by TCID₅₀ measuring method usingagglutination reaction of chicken fresh erythrocyte (product of NipponBiotest Laboratories, Inc.) after adding each liquid to ESK cell andculturing 10 days.

EXAMPLE 1

After a composition consisting of 49 wt % of polyvinylidene fluorideresin (SOLEF1012, product of SOLVAY Company, Crystal melting point: 173°C.) and 51 wt % of dicyclohexyl phthalate (product of Osaka OrganicChemical Industry, Ltd., industrial grade product) was churned and mixedat 70° C. using a Henschel mixer, the mixture was cooled into the shapeof a powder and was supplied from the hopper and melt-blended using atwo-axis extruder (Laboplast mill MODEL 50C 150, product of Toyo SeikiSeisaku-Sho, Ltd.) at 210° C. so that the mixture was homogeneouslydissolved. Then, the solution was extruded in the shape of a hollowfiber from a spinneret which consists of an annular orifice with aninner diameter of 0.8 mm and an outer diameter of 1.1 mm at adischarging rate of 17 m/min while passing through the inside hollowpart dibutyl phthalate (product of Sanken Kakoh Company) at atemperature of 130° C. at a rate of 8 ml/min. The extruded solution wascooled and solidified in a water bath heat-controlled to 40° C. androlled up to a spinner at a rate of 60 m/min. Then dicyclohexylphthalate and dibutyl phthalate were extracted and removed with 99%methanol modified ethanol (product of Imazu Chemical Co., Ltd.,industrial grade product) and the attached ethanol was replaced withwater, and a heat-treatment at 125° C. was conducted for 1 hour usinghigh-pressure steamy sterilization equipment (HV-85, product of HirayamaFactory, Ltd.) in the state where it was immersed in water. Then, afterreplacing attached water with ethanol, hollow fiber microporous membranewas obtained by drying at a temperature of 60° C. in the oven. In orderto prevent contraction during the steps from the extraction step todrying step, the membrane was fixed in a fixed size state and processed.

Then, hydrophilizing treatment by the graft method was performed to theabove microporous membrane. Hydroxypropyl acrylate (product of TokyoChemicals, Ltd., reagent grade) was dissolved in 25 vol % solution of3-butanol (Pure Science, Ltd., special reagent grade) so that the formermight be 8 vol %. The mixture was held at 40° C. while subjected tonitrogen bubbling for 20 minutes, and then used as a reaction liquid.First, 100 kGy irradiation of γ-ray was carried out by using Co60 as aradiation source, while cooling the microporous membrane at —60° C. withdry ice under nitrogen atmosphere. After allowing to stand still theirradiated membrane-under a reduced pressure of 13.4 Pa or less for 15minutes, it was contacted with the above-described reaction liquid andthe membrane was allowed to stand still at 40° C. for 1 hour. Then, themembrane was washed with ethanol, vacuum drying at 60° C. was performedfor 4 hours, and the microporous membrane was obtained. It was confirmedthat water spontaneously permeates into the pores when the obtainedmembrane was contacted with water. As a result of evaluating theperformance of the obtained membrane, high performance was shown as inTable 1.

EXAMPLE 2

A hollow fiber microporous membrane was obtained according to Example 1except that a composition consisting of 39 wt % of polyvinylidenefluoride resin and 61 wt % of dicyclohexyl phthalate was extruded from aspinneret which consists of an annular orifice with an inner diameter of0.8 mm and an outer diameter of 1.2 mm.

Then, the above microporous membrane was subjected to hydrophilizingtreatment according to Example 1. As a result of evaluating theperformance of the obtained membrane, high performance was shown as inTable 1.

EXAMPLE 3

A hollow fiber microporous membrane was obtained according to Example 2except that a composition consisting of 46 wt % of polyvinylidenefluoride resin and 54 wt % of dicyclohexyl phthalate was homogeneouslydissolved and the solution was extruded in the shape of a hollow fiberfrom a spinneret which consists of an annular orifice with an innerdiameter of 0.8 mm and an outer diameter of 1.2 mm at a discharging rateof 5.5 m/min while passing through the inside hollow part diphenylcresylphosphate (product of Daihachi Chemical Industry Co., Ltd., industrialgrade product) at a rate of 7 ml/min.

Then, the above microporous membrane was subjected to hydrophilizingtreatment according to Example 1. As a result of evaluating theperformance of the obtained membrane, high performance was shown as inTable 1.

EXAMPLE 4

Hydrophilizing treatment was performed to the membrane obtained inExample 1. The hydrophilizing treatment was performed according toExample 1 except that 7.52 vol % of hydroxypropyl acrylate, 0.15 vol %(1 mol % to hydroxypropyl acrylate) of polyethylene glycol diacrylate(product of Aldrich Co., average molecular weight 258) and 0.33 vol % (1mol % to hydroxypropyl acrylate) of polyethylene glycol diacrylate(product of Aldrich Co., average molecular weight 575) were dissolved in25 vol % solution of 3-butanol and used as a reaction liquid. As aresult of evaluating the performance of the obtained membrane, highperformance was shown as in Table 1.

EXAMPLE 5

Hydrophilizing treatment was performed to the membrane obtained inExample 1. The hydrophilizing treatment was performed according toExample 1 except that 4-hydroxybutyl acrylate (product of TokyoChemicals Industry) was dissolved in 25 vol % solution of 3-butanol sothat the former might be 8 vol % and used as a reaction liquid. As aresult of evaluating the performance of the obtained membrane, highperformance was shown as in Table 2.

EXAMPLE 6

A hollow fiber microporous membrane was obtained according to Example 1except that a composition consisting of 48 wt % of polyvinylidenefluoride resin and 52 wt % of dicyclohexyl phthalate was homogeneouslydissolved and the solution was extruded in the shape of a hollow fiberfrom a spinneret which consists of an annular orifice with an innerdiameter of 0.8 mm and an outer diameter of 1.05 mm at a dischargingrate of 20 m/min while passing through the inside hollow part dibutylphthalate at a rate of 10 ml/min. Then, the above microporous membranewas subjected to hydrophilizing treatment according to Example 1. As aresult of evaluating the performance of the obtained membrane, highperformance was shown as in Table 2.

EXAMPLE 7

A hollow fiber microporous membrane was obtained according to Example 1except that a composition consisting of 50 wt % of polyvinylidenefluoride resin and 50 wt % of dicyclohexyl phthalate was used.

Then, the above microporous membrane was subjected to hydrophilizingtreatment according to Example 1. As a result of evaluating theperformance of the obtained membrane, high performance was shown as inTable 2.

COMPARATIVE EXAMPLE 1

Hydrophilizing treatment was performed to the membrane obtained inExample 1 according to Example 1 except that 1.23 vol % of hydroxypropylacrylate, 0.61 vol % (25 mol % to hydroxypropyl acrylate) ofpolyethylene glycol diacrylate (product of Aldrich Co., averagemolecular weight 258), 1.36 vol % (25 mol % to hydroxypropyl acrylate)of polyethylene glycol diacrylate (product of Aldrich Co., averagemolecular weight 575) was dissolved in 25 vol % solution of 3-butanoland used as a reaction liquid. As a result of evaluating the performanceof the obtained membrane, as shown in Table 3 it turns out that thedecrease in the filtration rate of 3% bovine immunoglobulin solutionwith time is remarkable. It is considered that this was because thehydrophilizing treatment was performed using a reaction liquidcontaining a lot of cross-linking agent, and even though a sufficientcoarse structure layer for the membrane exists, the filtration rate wasreduced by adsorption of globulin.

COMPARATIVE EXAMPLE 2

A hollow fiber microporous membrane was obtained according to Example 1except that a composition consisting of polyvinylidene fluoride resinand dicyclohexyl phthalate was homogeneously dissolved and the solutionwas extruded in the shape of a hollow fiber from a spinneret whichconsists of an annular orifice with an inner diameter of 0.8 mm and anouter diameter of 1.2 mm at a discharging rate of 5.5 m/min whilepassing through the inside hollow part diheptyl phthalate at a rate of 7ml/min.

Then, the above microporous membrane was subjected to hydrophilizingtreatment. The hydrophilizing treatment was performed according toExample 1 except that hydroxypropyl acrylate and polyethylene glycoldimethacrylate (product of Aldrich Co., average molecular weight 550)was dissolved in 25 vol % solution of 3-butanol so that the acrylate andthe dimethacrylate might respectively be 1.1 vol % and 0.6 vol %. It wasconfirmed that water spontaneously permeates into the pores when theobtained membrane was contacted with water. As a result of evaluatingthe performance of the obtained membrane, as shown in Table 3 it turnsout that the permeation ability of 3% bovine globulin was very low.

EXAMPLE 8

As a result of evaluating the removing ability of porcine parvovirus ofthe hydrophilic microporous membrane obtained in Example 1, highperformance was exhibited as shown in Table 4.

EXAMPLE 9

As a result of evaluating the removing ability of porcine parvovirus ofthe hydrophilic microporous membrane obtained in Example 4, highperformance was exhibited as shown in Table 4.

EXAMPLE 10

As a result of evaluating the removing ability of porcine parvovirus ofthe hydrophilic microporous membrane obtained in Example 5, highperformance was exhibited as shown in Table 4.

EXAMPLE 11

As a result of evaluating the removing ability of porcine parvovirus ofthe hydrophilic microporous membrane obtained in Example 6, highperformance was exhibited as shown in Table 4.

EXAMPLE 12

As a result of evaluating the removing ability of porcine parvovirus ofthe hydrophilic microporous membrane obtained in Example 7, highperformance was exhibited as shown in Table 4.

TABLE 1 Items Example 1 Example 2 Example 3 Example 4 Form ofmicroporous Hollow fiber Hollow fiber Hollow fiber Hollow fiber membraneInner diameter (μm) 326 331 301 326 Thickness of membrane (μm) 72 70 3072 Thickness of coarse 16 14 3 16 structure layer (μm) Ratio of finestructure 76 80 90 76 layer (%) Graft ratio (%) 12 11 10 10 Maximum poresize (nm) 32 51 38 32 Water permeativity 8.3E-11 2.3E-10 2.4E-10 7.7E-11(m³/m²/second/Pa) Receding contact angle 0 0 0 0 (deg) Amount ofadsorption of 0 0 0 0 globulin (mg/g) Globulin permeation rate A 60 17286 48 (liter/m²/h) Globulin permeation rate B 46 151 26 21 (liter/m²/h)B/A 0.77 0.88 0.30 0.44 Permeation volume of 3 wt % 122 bovineimmunoglobulin solution (liter/m²/h)

TABLE 2 Items Example 5 Example 6 Example 7 Form of microporous Hollowfiber Hollow fiber Hollow fiber membrane Inner diameter (μm) 326 347 332Thickness of membrane (μm) 72 65 70 Thickness of coarse 16 15 15structure layer (μm) Ratio of fine structure 76 77 77 layer (%) Graftratio (%) 24 12 12 Maximum pore size (nm) 32 35 30 Water permeativity9.0E-11 8.5E-11 6.2E-11 (m³/m²/second/Pa) Receding contact angle 8.13 00 (deg) Amount of adsorption of 0 0 0 globulin (mg/g) Globulinpermeation rate A 48 61 54 (liter/m²/h) Globulin permeation rate B 23 4930 (liter/m²/h) B/A 0.48 0.80 0.55 Permeation volume of 3 wt % 140 79bovine immunoglobulin solution (liter/m²/h)

TABLE 3 Comparative Comparative Items Example 1 Example 1 Form ofmicroporous Hollow fiber Hollow fiber membrane Inner diameter (μm) 326302 Thickness of membrane (μm) 72 34 Thickness of coarse 16 6 structurelayer (μm) Ratio of fine structure 76 82 layer (%) Graft ratio (%) 8 10Maximum pore size (nm) 32 33 Water permeativity 9.1E-11 8.2E-11(m³/m²/second/Pa) Receding contact angle 23.2 0 (deg) Amount ofadsorption of 0 0 globulin (mg/g) Globulin permeation rate A 54 87(liter/m²/h) Globulin permeation rate B 8 8 (liter/m²/h) B/A 0.15 0.09

TABLE 4 Items Example 8 Example 9 Example 10 Example 11 Example 12Logarithmic reduction value 5.3 4.2 4.9 3.8 5.6 of porcine parvovirus (0to 55 liter/m² filtered time) Logarithmic reductionvalue >6.6 >6.6 >6.6 >6.6 >6.6 of porcine parvovirus (0 to 5 liter/m²filtered time) Logarithmic reduction value 3.8 3.6 3.7 3.4 4.4 ofporcine parvovirus (50 to 55 liter/m² filtered time)

INDUSTRIAL APPLICABILITY

According to the hydrophilic microporous membrane of the presentinvention, a separation membrane can be provided which can attain bothvirus removal performance and permeation capability of physiologicallyactive substances on a practical level in the filtration of medicalsupplies which may have a risk of virus contamination or physiologicallyactive substance solution which is the material thereof.

1. A hydrophilic microporous membrane comprising a thermoplastic resin,having been contacted with a hydrophilic vinyl monomer having one vinylgroup after generation of radicals by irradiation with ionizingradiation in order to be subjected to hydrophilizing treatment by agraft polymerization reaction, and having a maximum pore size of 10 to100 nm, wherein said hydrophilic microporous membrane has a coarsestructure layer with a higher open pore ratio and a fine structure layerwith a lower open pore ratio which are formed in one piece, wherein saidcoarse structure layer exists on at least one side of the membranesurface and has a thickness of 2 μm or more and a thickness of said finestructure layer is 50% or more of the whole membrane thickness, whereinwhen 3 wt % bovine immunoglobulin having a monomer ratio of 80 wt % ormore is filtered at a constant pressure of 0.3 MPa, an average globulinpermeation rate A (liter/m²/h) for 5 minutes from the start offiltration satisfies the following formula (1) and an average globulinpermeation rate B (liter/m²/h) for 5 minutes from the time point of 55minutes after the start of filtration satisfies the following formula(2):Globulin permeation rate A>0.0015 maximum pore size (nm)^(2.75)  (1)Globulin permeation rate B/globulin permeation rate A>0.2  (2).
 2. Thehydrophilic microporous membrane according to claim 1 having a maximumpore size of 10 to 70 nm.
 3. The hydrophilic microporous membraneaccording to claim 2 having a receding contact angle of water of 0 to 20degrees.
 4. The hydrophilic microporous membrane according to claim 1having a maximum pore size of 10 to 36 nm.
 5. The hydrophilicmicroporous membrane according to claim 4 having a receding contactangle of water of 0 to 20 degrees.
 6. The hydrophilic microporousmembrane according to claim 4, wherein an accumulated permeation volumein three hours after the start of filtration is 50 liter/m² or more when3 wt % bovine immunoglobulin having a monomer ratio of 80 wt % or moreis filtered at a constant pressure of 0.3 MPa.
 7. The hydrophilicmicroporous membrane according to claim 1 having a receding contactangle of water of 0 to 20 degrees.
 8. The hydrophilic microporousmembrane according to claim 1, wherein a logarithmic reduction value ofporcine parvovirus at the time point by which 55 liter/m² has beenpermeated from the start of filtration is 3 or more.
 9. The hydrophilicmicroporous membrane according to claim 1, wherein both of a logarithmicreduction value of porcine parvovirus at the time point by which 5liter/m² has been permeated from the start of filtration and alogarithmic reduction value of porcine parvovirus at the time point bywhich further 5 liter/m² has been permeated after 50 liter/m² ispermeated are 3 or more.
 10. The hydrophilic microporous membraneaccording to claim 9, wherein an accumulated permeation volume in threehours after the start of filtration is 50 liter/m² or more when 3 wt %bovine immunoglobulin having a monomer ratio of 80 wt % or more isfiltered at a constant pressure of 0.3 MPa.
 11. The hydrophilicmicroporous membrane according to claim 1, wherein an accumulatedpermeation volume in three hours after the start of filtration is 50liter/m² or more when 3 wt % bovine immunoglobulin having a monomerratio of 80 wt % or more is filtered at a constant pressure of 0.3 MPa.12. The hydrophilic microporous membrane according to claim 1, whereinthe thickness of the coarse structure layer is 3 μm or more.
 13. Thehydrophilic microporous membrane according to claim 1, wherein thethickness of the coarse structure layer is 5 μm or more.
 14. Thehydrophilic microporous membrane according to claim 1, wherein thethermoplastic resin is polyvinylidene fluoride.
 15. The hydrophilicmicroporous membrane according to claim 1, wherein the hydrophilizingtreatment is a graft polymerization reaction of a hydrophilic vinylmonomer having one vinyl group to the surface of the pores of thehydrophilic microporous membrane.
 16. The hydrophilic microporousmembrane according to claim 15, wherein the hydrophilic vinyl monomercontains a hydroxyl group.
 17. The hydrophilic microporous membraneaccording to claim 1, wherein the adsorption amount per 1 g of themembrane is 3 mg or less when dead-end filtration at a constant pressureof 0.3 MPa is performed using a 0.01 wt % bovine immunoglobulin solutionand a filtrate of 50 liter/m² from the start of filtration is collected.18. A method for removing a virus from a liquid containing aphysiologically active substance, comprising filtering the liquidthrough the hydrophilic microporous membrane according to claim 1.